Molecular Dynamics Studies Of The Impact Of Environments On Structure Of Chimera C3of Human β-defensins2and3

In the field of life science, the relationship between biomolecular structure(conformation) and function has been an essential and basic problem. A lot ofexperimental researches provide persuasive evidence that conformational change ofprotein is a dynamic process, which is important for playing their physiological roles.The dynamic behaviors of protein are involved in almost all biological processes,such as drug delivery, enzymatic catalysis, and molecular recognition and so on. Since1990s, with the rapid development of computer science, theoretical calculationmethod has got a lot of progress. Molecular dynamics simulation is considered one ofpivotal methods for studying the dynamic processes of biological systems and theirmechanism; it can offer us much valuable information for comprehending andrevealing the crucial rules of life phenomenon from molecular subunits or evenatomic level, and can also provide the experimental studies with advantageouslytheoretical support. In this thesis work, we have systematically studied the impact ofenvironments on the structure of chimera C3of human-defensins2and3by themeans of molecular dynamics simulations. The simulative results are good inagreement with the previous experimental results and also establish the importanttheoretical basis to understand the antimicrobial mechanism of antimicrobial peptideswhich contain the secondary structure of-sheets. The main content of our work is asfollows:C3is a chimera from HBD2and HBD3and possesses higher antimicrobial activitycompared with its parental molecules, so it is an attractive candidate for clinicalapplication of antimicrobial peptides. In continuation with the previous studies, molecular dynamics simulations were carried out for further investigating the effect ofambient environments (temperature and bacterial membrane) on C3dynamics. Ourresults reveal that C3has higher flexibility, larger intensity of motion and morerelevant secondary structural changes at363K to adapt the high temperature andmaintain its structural stability, in comparison with it at293K; when C3moleculeassociates with the bacterial membrane, it slightly fluctuates and undergoes localconformational changes; in summary, C3molecule demonstrates stable conformationsunder high temperature and membrane environment. Furthermore, MD resultsanalysis show that the hydrophobic contacts, the hydrogen bonds and disulfide bondsin the peptide are responsible for maintaining its stable conformation. In addition, oursimulation shows that C3peptides can make anionic lipids clustered in the bacterialmembrane, which lead to the decrease of membrane stability; it means that positivecharges and pronounced regional cationic charge density of C3are most key factorsfor its antimicrobial activity. Our work also contributes to further understanding thestructures and dynamics of other chimeras of human-defensins.